Reversal of morphine-induced respiratory depression with the µ₁-opioid receptor antagonist naloxonazine engenders excitation and instability of breathing

The administration of opioid receptor antagonists is believed to overcome ventilatory depressant effects of opioids. Here we show that many ventilatory depressant effects of morphine are converted to excitatory responses after µ₁-opioid receptor blockade, and that these responses are accompanied by ventilatory instability. In this study, we report <i>1</i>) ventilatory responses elicited by morphine (10 mg/kg, iv) and <i>2</i>) ventilatory responses elicited by a subsequent hypoxic-hypercapnic (HH) gas challenge and return to room air in male Sprague Dawley rats pretreated with <i>1</i>) vehicle, <i>2</i>) the centrally acting selective µ₁-opioid receptor antagonist, naloxonazine (1.5 mg/kg, iv), or <i>3</i>) the centrally acting (delta 1,2) δ_1,2-opioid receptor antagonist, naltrindole (1.5 mg/kg, iv). The morphine-induced decreases in frequency of breathing, peak inspiratory flow, peak expiratory flow, expiratory flow at 50% expired TV, inspiratory drive, and expiratory drive in vehicle-treated rats were converted to profound increases in naloxonazine-treated rats. Additionally, the adverse effects of morphine on expiratory delay and apneic pause were augmented in naloxonazine-treated rats, and administration of morphine increased ventilatory instability (i.e., noneupneic breathing index) in naloxonazine-treated rats, which was not due to increases in ventilatory drive. Subsequent exposure to a HH gas challenge elicited qualitatively similar responses in both groups, whereas the responses upon return to room air (e.g., frequency of breathing, inspiratory time, expiratory time, end expiratory pause, relaxation time, expiratory delay, and noneupneic breathing index) were substantially different in naloxonazine-treated versus vehicle-treated rats. The above mentioned effects of morphine were only marginally affected in naltrindole-treated rats. These novel data highlight the complicated effects that µ₁-opioid receptor antagonism exerts on the ventilatory effects of morphine.<b>NEW & NOTEWORTHY</b> This study shows that the systemic injection of morphine elicits a pronounced overshoot in ventilation in freely-moving Sprague Dawley rats pretreated with the centrally-acting selective µ₁-opioid receptor antagonist, naloxonazine, but not with the centrally-acting δ_1,2-opioid receptor antagonist, naltrindole. This suggests that morphine can recruit a non-µ₁-opioid receptor system that promotes breathing.